Lecture 6: Complement Flashcards
the complement system consists of approximately ___ pre-made proteins and membrane components
50
the complement system is activated by sequential _____ of substrates that results in a ____ reaction
proteolytic cleavage; cascade
what are 4 functions of the complement system?
- lyse target cells
- promote phagocytosis (opsonization)
- induce inflammatory responses (anaphylatoxins)
- clear immune complexes (phagocytes)
what are the 3 pathways of activation of the complement system?
- classical
- alternative
- lectin
what is the only stage of the cascade that differs between the classical, alternative and lectin pathways?
the initiation
once you arrive at ___, the cascade is the same for all three complement pathways
C3 convertase
in the complement system, all roads lead to the C3 convertase; which lyses C3 into ___ and ___
C3a and C3b
C3 is also known as ____ and is the ___ (active or inactive) form and is cleaved into C3a and C3b which are the ____(active or inactive) form
zymogen; inactive; active
the C3b fragment complexes with ____ to create C5 convertase
C3 convertase (C4b2A or C3bBb)
the C3a fragment has what role?
it is an anaphylatoxin (driver of inflammation)
if C5 convertase complexes with C3bBb, what pathway will be taken>
alternative
what is the role of the C5b fragment?
binds to the cell membrane to permit formation of the membrane attack complex (MAC)
what is the role of the C5a fragment?
anaphylatoxin (driver of inflammation)
what is the role C6 in the MAC complex?
stabalizes the C5b
what is the function of the C7 in the MAC?
binds C5bC6 and inserts into the cell membrane
what is the function of C8 in MAC?
binds C5bC6C7 and creates a pore in the cell membrane
what is the function of C9 in the MAC?
there are typically 10-15 per MAC and they bind the C5cC6C7C8 and make a large pore in the membrane
what is the role of the alternative complement pathway?
involved in innate immunity and functions in the absence of specific antibody
what are 2 mechanisms for activation of the alternative complement pathway?
- spontaneous hydrolysis of C3 (tickover or fluid-phase C3 convertase)
- by pathogens or other serum proteins (like clotting cascade components)
activation of the classical pathway requires one or more ___
antibody-antigen complexes containing IgM or IgG binding to C1q
what causes the activation of the lectin pathway?
binding of mannose-binding lectin (MBL) to mannose residues and carbohydrates on certain microbes
what is MBL (mannose binding lectin)?
a serum protein
does the lectin complement pathway depend on antobodies?
no
explain the lectin complement pathway
MBL-associated serine proteases (MASP-1 and MASP-2) bind MBL on the microbe surface, forming a complex that is able to cleave C4 and C2 to make C4b2a = C3 convertase
what are 3 examples of innate defence complement activity?
- membrane attack complex-mediated lysis of micribes (C5b-C9)
- opsonization (C3b and IgG)
- introduction of inflammation and chemotaxis by anaphylatoxins
with anaphylatoxins, activation of the inflammatory response by C3a and C5a occurs via ___ and _____
chemoattraction and mast cell degranulation
what are the 4 biological functions of complement?
- cell lysis by MAC
- opsonization
- anaphylatoxins
- virus neutralazation
what does the complement system use for cell lysis?
MAC
what does the complement system use for opsonization and phagocytosis?
- opsonization: C3b, iC3b and C4b promote phogocytosis
2. C5a activates phagocytes
clearance of particulate immune complexes occurs by what process?
phagocytosis
soluble immune complex clearance is caused by an interaction of ___ and ___ on red blood cells
C3b and CR1
what molecules are anaphylatoxins?
C3a, C4a and C5a
which anaphylatoxins are chemotractant for granulocytes and monocytes and also cause platelet aggregation?
C3a and C5a
how does the complement system cause virus neutralization?
by aggregation, opsonization and lysis (of envelopoed viruses) to reduce infectivity
what is the function of the CR1?
clearnace of immune complexes, enhancement of phagocytosis, regulation of C3 breakdown
what is the function of CR3?
binding to adhesion molecules on leukocytes, facilitates extravasation; iC3b binding enhances opsonization of immune complexes
what is the function of CR4?
ic3b mediated phagocytosis
what is the function of C3aR?
induces degranulation
what is the function of C5aR?
induces degranulation, chemoattraction, acts with IL-1B and or TNF-a to induce acute phase response; induces respiratory burst in neutrophils
The ____ nature of many complement components ensures that only appropriate targets such as invading micribes are attacked by the complement system
labile (easily broken down)
the complement system is subject to ____ which competes against complement in order to prevent excessive activation
active regulation
t/f active regulation can happen at several points in the compliment pathway
t
what are the 5 approaches to regulating complement?
- dissociation of C1 components
- factor 1 cofactor activity
- decay-accelerating activity for C3 convertase
- inhibition of lysis
- cleavage of anaphylatoxins
what is the function of C1 inhibitor (C1INH)?
induces dissociation and inhibition of C1r2s2 from C1q; serine protease inhibitor
is C1 inhibitor a fluid phase or a membrane protein?
fluid phase
which pathways are affected by C1 inhibitor?
classical and lectin
what is the function of decay-accelerating factor (DAF) CD55?
accelerates the dissociation of C4b2a and c3bBb C3 convertase
is DAF fluid phase or membrane protein?
membrane bound
what pathways are affected by DAF?
classical, alternative and lectin (all of them)
what is teh function of factor H?
blocks the formation of, or quickens the dissociation of C3bBb C3 convertase
what pathways are affected by factor H?
alternative
is factor H a membrane or fluid phase protein?
soluble
what is teh function of factor I?
serine protease; cleaves C4b and C3b using cofactors
what pathways are affected by factor I?
classical, alternative, and lectin (all of them)
what is the function of protectin (CD59)?
binds C5b678 on host cells, blocking binding of C9 and the formation of the MAC complex
what pathways are affected by protectin?
all
is protectin membrane or soluble protein?
membrane
what is the function of the carbopeptidases N, B and R ?
cleave and inactivate the anaphylatoxins C3a and C5a
what pathways are affected my carboxypeptidases?
all that produce anaphylatoxins
are carboxypeptidases soluble or membrane proteins?
soluble
t/f the alternate and lectin pathways need to have previous exposure to the pathogen to activate, while the classical pathway does not
t
